Gabapentin, a generic name for 1-(aminomethyl)-1-cyclohexaneacetic acid (I), first disclosed in U.S. Pat. No. 4,024,175 by Warner-Lambert Co., is a very useful therapeutic agent for cerebral disorders with extremely low toxicity in human.
There are a number of patented processes for manufacturing this compound. Typical processes are exemplified by U.S. Pat. Nos. 4,024,175, 6,518,456, WO02/34709, WO2004046108, Indian patent 186285, U.S. Pat. Nos. 5,319,135, 5,091,567, and WO 9914184.
U.S. Pat. Nos. 4,024,175 and 4,087,544 disclosed that 1-aminomethyl-1-cyclopentane-acetic acid hydrochloride can be prepared by treating 1,1-cyclopentane-diacetic acid monoamide with NaOH/NaBrO followed by HCl. 1,1-cyclopentane-diacetic acid monoamide hydrochloride was obtained by passing the gabapentin HCl salt through an anion exchange column. However, no yield and purity was reported in these patents. Following similar procedures, except with a cation exchange resin for the last step, WO 02/34709 disclosed a method for the preparation of gabapentin with as much as 80% yield. However, the purity of the product again was not disclosed. These methods require a large amount of solvents for the ion exchange process.

A very useful improvement on the process of converting gabapentin HCl salt into gabapentin was disclosed in U.S. Pat. No. 6,518,456, in which gabapentin HCl salt was neutralized with a base, such as NaOH, to the isoelectric point of gabapentin, i.e., pH=7.1-7.2, thus allowing the precipitation and isolation monohydrate via filtration of crude gabapentin monohydrate (Ia) (Scheme 2). The crude gabapentin monohydrate can then be converted to gabapentin in alcohol/ether mixture. This process represents a major advancement for the isolation of gabapentin, avoiding the solvent-consuming ion exchange column chromatography method, although it needed very careful control of the amount and rate of the base added so that the pH of the solution would not fall out of the narrow range of 7.1-7.2.
In Indian patent 186,285, cyclohexane 1,1-diacetic acid monoamide (II) was converted into 3,3-pentamethylenebutyrolactam (IV) through the treatment with NaOH/Br2, although no yield or purity of the lactam was reported. Subsequently, the lactam IV was converted to gabapentin HCl salt (III), which was turned into gabapentin (I) by slowly neutralizing gabapentin HCl salt (III) with NaOH solution to pH between 7.4-7.8 (Scheme 3) for the isolation of gabapentin (I). The neutralization process needed to be very well controlled and took about 6 hours. WO 2004046108 disclosed an improved process for the first step, reaching a yield as high as 82%. These processes use bromine, a very corrosive chemical, which erodes manufacturing facilities and releases harmful fumes into the working environment, and thus not ideal for industrial scale application.
Other processes, exemplified by U.S. Pat. No. 5,091,567, WO 9914184 (Scheme 4), and U.S. Pat. No. 5,319,153 (Scheme 5), require catalytic hydrogenation of intermediates at elevated pressure and sometimes elevated temperatures.

Thus, there remains a need for new and improved methods of manufacturing gabapentin (I) from, e.g., cyclohexane 1,1-diacetic acid monoamide (II), a mass produced feed stock that is mass produced.
It has been shown that of 3,3-pentamethylenebutyrolactam (IV) can be formed during storage of gabapentin (I) for unknown reasons. The cytotoxicity of IV (LD50=300 mg/kg) is much higher than that of gabapentin (I) (LD50>8000 mg/Kg) [U.S. Pat. No. 6,054,482]. Therefore, not only the initial content of IV must be controlled at less than 0.5%, but also the formation of IV from gabapentin (I) must be minimized for safety reason. Thus, another needed improvement is to manufacture stable gabapentin (I) under storage conditions. The formation of 3,3-pentamethylenebutyrolactam (IV) is a competing side reaction during the neutralization of gabapentin HCl salt (III) as well as during the dehydration process of gabapentin hydrate. Thus, yet another needed improvemetn is to recover as much 3,3-pentamethylenebutyrolactam (IV) as possible to reduce the loss of useful intermediates and increase the yield of the final product.